Discovery and Optimization of a Novel Series of Potent Mutant B‑Raf^V600E Selective Kinase Inhibitors

B-Raf represents an attractive target for anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-Raf^V600E kinase activity both in vitro and in vivo. Investigations into the structure–activity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-Raf^V600E in vitro and showed preferential antiproliferative activity in mutant B-Raf^V600E cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-Raf^V600E A375 xenograft in vivo at a well-tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in nonmutant B-Raf cell lines in vitro